Tau(273-284): A Molecular Dynamics Study of Intrinsically Disordered Protein Conformations in the Presence of Osmolytes

Abstract

In contrast to traditional protein structural paradigms, intrinsically disordered proteins (IDPs) represent a unique class of proteins which have very few stable secondary structures. This inherent disorder in native structure allows IDPs to adopt a wide variety of extended and compact conformations upon binding to nearby macromolecules which enable them to perform a large number of vital physiological functions. Here we focus on the microtubule associated tau protein, a classic example of a highly-soluble IDP which helps regulate microtubule growth in the brain. Dysfunctions in tau (i.e. taupathies) are often implicated in Alzheimer's disease and other forms of dementia, as large quantities of tau cross-beta sheets can accumulate and potentially inhibit proper brain function, in additional to deregulating further microtubule growth. Our work builds on our previous studies [1] where we investigated the conformational properties of a fragment of tau which is highly associated with aggregation, specifically the R2/wt tau residues 273-284 (sequence GKVQIINKKLDL). Here we use replica exchange molecular dynamics to study the effect of two important osmolytes, trimethylamine n-oxide (TMAO) and urea, on the folding and aggregation of R2/wt. The overarching goal of our study is aimed at understanding what factors facilitate or inhibit tau aggregation, and identifying (to the extent possible) what physiological factors affect the folding of IDPs since there is still a considerable amount of information to be learned about how these proteins operate in the human body.[1] L. Larini, M. M. Gessel, N. E. LaPointe, T. D. Do, M. T. Bowers, S. C. Feinstein, and J. E. Shea, “Initiation of assembly of tau(273-284) and its Delta K280 mutant: an experimental and computational study,” Physical Chemistry Chemical Physics 15 (23), 8916-8928 (2013).